Triaryl-sulphonium compounds, kit and methods for labeling positron emitting isotopes

Abstract

This invention relates to novel compounds suitable for labeling by positron emitting isotopes, such as 18 F, 11 C, 13 N and 15 O, through appropriate labeling reagents, such as 18 F reagents and methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by positron emission tomography (PET).

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         wherein A, A′ and Q are independently at each occurrence and individually selected from the group comprising aryl, substituted aryl, heteroaryl and substituted heteroaryl, 
         wherein optionally either A and A′ A and Q or A′ and Q are linked to each other via R 4 , 
         wherein, when substituted, there is one substituent or several substituents on said aryl or said heteroaryl, and the one or several substituent(s) is (are) located at any position of said aryl or heteroaryl, 
         wherein S is sulfur, 
         wherein X −  is selected from the group comprising a corresponding base of an inorganic acid and a corresponding base of an organic acid, 
         wherein L-M-Y—Z is selected from the group comprising a bond and a linker, said bond being selected from a single, double or triple bond, said bond connecting E to Q, said linker connecting E to Q, 
         wherein E is a targeting agent, 
         R 4  being selected from the group comprising: bond, oxygen atom, sulphur atom, (N-alkyl) nitrogen, in particular (N—(C 1 -C 4 )alkyl)nitrogen, (C 1 -C 3 )alkylene, and (C 2 -C 3 )alkylene, and 
         including all isomeric forms of said compound, including but not limited to enantiomers and diastereoisomers as well as racemic mixtures; 
         and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof. 
       
     
     
         2 . A method for obtaining compounds of Formula II
   F-Q 2 -L-M-Y—Z-E  II
   wherein A, A′ and Q 2  are independently at each occurrence and individually selected from the group comprising aryl, substituted aryl, heteroaryl and substituted heteroaryl, wherein optionally either A and A′, A and Q 2  or A 1  and Q 2  are linked to each other via R 4 ,   wherein, when substituted, there is one substituent or several substituents on said aryl or said heteroaryl, and the one or several substituent(s) is (are) located at any position of said aryl or heteroaryl,   wherein S is sulfur,   wherein X −  is selected from the group comprising a corresponding base of an inorganic acid and a corresponding base of an organic acid,   wherein L-M-Y—Z is selected from the group comprising a bond and a linker, said bond being selected from a single, double or triple bond, said bond connecting E to Q 2 , said linker connecting E to Q 2 ,   wherein E is a targeting agent, and   R 4  being selected from the group comprising: bond, oxygen atom, sulphur atom, (N-alkyl) nitrogen, in particular (N—(C 1 -C 4 )alkyl)nitrogen, (C 1 -C 3 )alkylene, and (C 2 -C 3 )alkylene, and   Q 2  is Q   comprising the step
 Reacting compound of Formula I with fluorination agent. 
   
     
     
         3 . A compound according to formula III 
       
         
           
           
               
               
           
         
         wherein A, A′, S, Q, L, X −  and M are as defined above, and 
         wherein FG 1  is selected from the group comprising 
         a) hydroxy, 
         b) iodo, 
         c) bromo, 
         d) chloro, 
         e) N 3 , 
         f) C≡CH, 
         g) C(O)OR 3 , 
         h) active ester moiety, 
         i) C(O)-Hal, 
         j) NHR 1 , 
         k) N═C═O, 
         l) N═C═S, 
         m) O—S(O) 2 -aryl, 
         n) OS(O) 2 -alkyl, 
         o) SO 2 -Hal, 
         p) S 3 H, 
         q) SH, 
         r) O—C(═O)-Hal, 
         s) O—C(═S)-Hal, 
         t) 
       
       
         
           
           
               
               
           
         
         u) 
       
       
         
           
           
               
               
           
         
         v) 
       
       
         
           
           
               
               
           
         
         w) 
       
       
         
           
           
               
               
           
         
         x) 
       
       
         
           
           
               
               
           
         
         y) 
       
       
         
           
           
               
               
           
         
       
       and
 z) 
 
       
         
           
           
               
               
           
         
         wherein R 1  is as defined above, and wherein R 3  is selected from the group comprising 
         a) hydrogen, 
         b) active ester moiety, 
         c) (C 1 -C 6 )alkyl, 
         d) (C 2 -C 6 )alkenyl and 
         e) aryl alkyl; and
 wherein Hal is a halogen, such as F, Cl, Br or I 
 including all isomeric forms of said compound, including but not limited to enantiomers and diastereoisomers as well as racemic mixtures; 
 and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof. 
 
       
     
     
         4 . A method for obtaining compounds of Formula IV
     18 F-Q 2 -L-M-FG 1   IV
   wherein   Q 2  is Q;   L is selected from the group comprising   a) —C(═O)H,   b) —S(═O) 2 H,   c) —S(═O)H,   d) —N(H)—C(═O)H and   e) —C≡C—C(═O)—,
 wherein L is in ortho, meta, para or any other position to S + ; and 
 M is selected from the group comprising 
   a) bond, said bond being selected from a single, double or triple bond,   b) —(CH 2 ) d —,   c) —(CH 2 ) d -D-(CH 2 ) d —,   d) —N(R 1 )—(CH 2 ) d — and   e) —N(R 1 )—(CH 2 ) p —(CH 2 —O—CH 2 ) k —(CH 2 ) p —;
 FG 1  is selected from the group comprising 
   a) hydroxy,   b) iodo,   c) bromo,   d) chloro,   e) N 3 ,   f) C≡CH,   g) C(O)OR 3 ,   h) active ester moiety,   i) C(O)-Hal,   j) NHR 1 ,   k) N═C═O,   l) N═C═S,   m) O—S(O) 2 -aryl,   n) OS(O) 2 -alkyl,   o) SO 2 -Hal,   p) S 3 H,   q) SH,   r) O—C(═O)-Hal,   s) O—C(═S)-Hal,   t)   
       
         
           
           
               
               
           
         
         u) 
       
       
         
           
           
               
               
           
         
         v) 
       
       
         
           
           
               
               
           
         
         w) 
       
       
         
           
           
               
               
           
         
         x) 
       
       
         
           
           
               
               
           
         
         y) 
       
       
         
           
           
               
               
           
         
       
       and
 z) 
 
       
         
           
           
               
               
           
         
         comprising the step
 Reacting compound of Formula III with fluorination agent. 
 
       
     
     
         5 . A method of preparing a compound according to formula I according to  claim 1 ,
 comprising the step
 Reacting a compound according to formula III with a compound according to formula V
   E-FG 2   V
 
 
   wherein FG 2  is identical to FG 1  and   E is a targeting agent.   
     
     
         6 . A compound according to  claim 1  wherein E is a peptide (or a peptidomimetic) or an oligonucleotide or a small molecule, 
     
     
         7 . A pharmaceutical composition comprising a compound according to formula I or III and a pharmaceutically acceptable carrier or diluent. 
     
     
         8 . A kit comprising a sealed vial containing a predetermined quantity of a compound according to formula I according to  claim 1  and/or a compound according to formula III 
       
         
           
           
               
               
           
         
         wherein A, A′, S, Q, L, X −  and M are as defined above, and 
         wherein FG 1  is selected from the group comprising 
         f) hydroxy, 
         g) iodo, 
         h) bromo, 
         i) chloro, 
         j) N 3 , 
         aa) C≡CH, 
         bb) C(O)OR 3 , 
         cc) active ester moiety, 
         dd) C(O)-Hal, 
         ee) NHR 1 , 
         ff) N═C═O, 
         gg) N═C═S, 
         hh) O—S(O) 2 -aryl, 
         ii) OS(O) 2 -alkyl, 
         jj) SO 2 -Hal, 
         kk) S 3 H, 
         ll) SH, 
         mm) O—C(═O)-Hal, 
         nn) O—C(═S)-Hal, 
         oo) 
       
       
         
           
           
               
               
           
         
         pp) 
       
       
         
           
           
               
               
           
         
         qq) 
       
       
         
           
           
               
               
           
         
         rr) 
       
       
         
           
           
               
               
           
         
         ss) 
       
       
         
           
           
               
               
           
         
         tt) 
       
       
         
           
           
               
               
           
         
       
       and
 uu) 
 
       
         
           
           
               
               
           
         
         wherein R 1  is as defined above, and wherein R 3  is selected from the group comprising 
         a) hydrogen, 
         b) active ester moiety, 
         c) (C 1 -C 6 )alkyl, 
         d) (C 2 -C 6 )alkenyl and 
         e) aryl alkyl; and
 wherein Hal is a halogen, such as F, Cl, Br or I 
 in one sealed vial or in separate sealed vial. 
 
       
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . A method of treating CNS diseases comprising administering an effective amount of a compound according to formula I of  claim 1 . 
     
     
         12 . A method of using a compound of Formula II of  claim 2  as an imaging agent comprising administering a compound of Formula II to a patient and imaging the patient. 
     
     
         13 . A method of treating CNS diseases comprising administering an effective amount of a compound according to formula II of  claim 2 . 
     
     
         14 . A method of treating CNS diseases comprising administering an effective amount of a compound according to formula III of  claim 3 . 
     
     
         15 . A method of treating CNS diseases comprising administering an effective amount of a compound according to formula IV of  claims 4 . 
     
     
         16 . A method of using a compound of Formula IV of  claim 4  as an imaging agent comprising administering a compound of Formula IV to a patient and taking an image of said patient.